A substantial percentage of HIV-1-infected subjects remain disease-free for many years with low viral load and intact lymph node architecture. Moreover, cohorts of HIV-1-exposed individuals who remain free of infection over a long period of viral exposure have been described. The molecular basis of this heterogeneous clinical presentation is unknown; one possibility is that differences in humoral immune responses to yet unrecognized epitopes may contribute to resistance to HIV infection or the development of a long-term non progressive state of HIV-1 infection. The aim of this project is to systematically compare the antibody specificity?s that are present in serum obtained from individuals with progressive and non-progressive HIV disease. To this end, Random Peptide Libraries (RPL) displayed on phages have been utilized; these libraries carry random sequences of nine residues expressed in frame with the pVIII coat protein of f11.1 filamentous phages. Twenty two long-term-non progressors (LTNP) and twenty five AIDS patients were enrolled in this study. After extensive counter- screening with normal sera, we identified several epitopes displayed on phages (phagotopes) that were recognized by antibodies from the HIV-infected patients. The selected phagotopes were specific for HIV-1+, and the extent of the phagotope reactivity with HIV-1+ sera waned with disease progression, suggesting a complex evolution of the antibody repertoire during HIV-1 infection. The amino acid sequence of some epitopes showed homology with HIV gp120 or gp41 protein domains, while the majority of them mimicked HIV-1 conformational epitopes. The serum antibodies, immunoaffinity purified by binding to each phagotope, reacted with HIV-1 proteins in ELISA and in immunoblotting, and this binding was specifically displaced by the phagotope utilized as a ligand and by the phage-displayed peptides. Furthermore, serum antibodies from monkeys infected with recombinant SHIV viruses strongly reacted with HIV-1-specific phagotopes. Collectively, the above results indicate that the phagotopes selected by phage display technology using patient sera are functionally mimotopes of HIV- 1 antigenic determinants. These epitopes are expected to be immunogenic, and to induce a HIV-1-specific antibody response in vivo. In fact, immunized mice developed a strong antibody response to the original epitopes utilized as immunogen. The epitope-specific antibodies immunoaffinity purified from immunized mice and from patient sera efficiently neutralized HIV- 1 isolates in vitro. Thus, a pool of HIV-1 mimotopes can be selected from RPLs, and may allow the formulation of innovative vaccine candidates offering protection against highly variable pathogens such as HIV-1.